Glycogen synthase kinase 3β is a natural activator of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1)

Glycogen synthase kinase 3β (GSK3β) is implicated in many biological events, including embryonic development, cell differentiation, apoptosis, and insulin response. GSK3β has now been shown to induce activation of the mitogen-activated protein kinase kinase kinase MEKK1 and thereby to promote signaling by the stress-activated protein kinase pathway. GSK3β-binding protein blocked the activation of MEKK1 by GSK3β in human embryonic kidney 293 (HEK293) cells. Furthermore, co-immunoprecipitation analysis revealed a physical association between endogenous GSK3β and MEKK1 in HEK293 cells. Overexpression of axin1, a GSK3β-regulated scaffolding protein, did not affect the physical interaction between GSK3β and MEKK1 in transfected HEK293 cells. Exposure of cells to insulin inhibited the activation of MEKK1 by GSK3β, and this inhibitory effect of insulin was abolished by the phosphatidylinositol 3-kinase inhibitor wortmannin. Furthermore, MEKK1 activity under either basal or UV- or tumor necrosis factor a-stimulated conditions was reduced in embryonic fibroblasts derived from GSK3β knockout mice compared with that in such cells from wild-type mice. Ectopic expression of GSK3β increased both basal and tumor necrosis factor a-stimulated activities of MEKK1 in GSK3β^-/- cells. Together, these observations suggest that GSK3β functions as a natural activator of MEKK1.